JPH1072441A - Production of pyridine-2,3-dicarboxylic ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as e.g. a herbicide by reaction between 2,3-dichloropyridine as a readily available starting material, carbon monoxide and an alcohol in the presence of a catalyst and a base. SOLUTION: This new compound is a pyridine-2,3-dicarboxylic ester of formula I (R is a 1-6C alkyl, a 3-6C cycloalkyl, etc.; R<1> to R<3> are each H, a 1-6C alkyl, etc.), e.g. 2,3-dichloro-5 (methoxymethyl)pyridine. The compound of formula I is obtained by reaction between a 2-halopyridine of formula II, CO and an alcohol of the formula ROH by the use of a catalyst, a catalytically active complex of Pd and a diphosphine of the formula R<7> R<5> P-Q-PR<6> R<7> [R<4> to R<7> are each phenyl, a 1-6C alkyl, etc.; Q is 1,1'-ferrocenediyl or [CH2 ]n ((n) is 3 or 4)], in the presence of a base (an alkali metal acetate) in an alcohol as solvent at 80-250 deg.C under a pressure of 1-50atm for several hours. In this case, the proportion of the Pd to be used to the halogen compound of formula II is 0.2-10mol%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to pyridine-2,3
A process for producing substituted diesters of dicarboxylic acids by reacting 2,3-dichloropyridine with carbon monoxide and an alcohol in the presence of a catalyst and a base.

[0002] The diesters prepared according to the present invention have the following general formula:

[0003]

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Wherein R is C _1-6 alkyl, C _3-6 cycloalkyl, aryl or arylalkyl;
R ¹ to R ³ independently of one another are hydrogen, C _1-6 alkyl, fluorinated C _1-6 alkyl, C _1-6 alkoxy,
(C _1-6 alkoxy) -C _1-6 alkyl or (C _1-6 alkoxy) -carbonyl. A number of compounds having this structure are important herbicides or building blocks for herbicide production (US-A
5288866). Known synthetic methods for these compounds include:
Usually, one starts from the corresponding carboxylic acid or carboxylic acid derivative (acid chloride, nitrile). Many of these raw materials are not readily available and are therefore expensive.

Another method for producing diethylpyridine-2,3-dicarboxylate (US Pat. No. 5,296,601)
Starts from 2,3-dichloropyridine, which is reacted with ethanol and carbon monoxide, a palladium complex containing 1,4-bis (diphenylphosphuno) butane as ligand, and sodium carbonate as base. The reaction gives the diester described above. However, the yield is very low (less than 3%), and it is quite uneconomical to apply this method to industrial practice.

It is therefore an object of the present invention to provide a process which gives high yields, starting from readily available starting materials.

[0007] According to the invention, this object is achieved by a method according to claim 1.

General formula

[0009]

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[Wherein, R ¹ to R ³ have the same meaning as described above. Wherein carbon monoxide and a general formula

[0011]

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[Wherein, R has the meaning described above. ], Palladium as a catalyst and a general formula

[0013]

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Wherein R ⁴ to R ⁷ are each independently
Phenyl, substituted phenyl, C _1-6 alkyl or C _3-6
Cycloalkyl, Q is 1,1'-ferrocene diyl group, or a group of the formula - [CH _{2] n} - (where, n represents 3 or 4.) Is a group. If a catalytically active complex with diphosphine is present, alkali metal and alkaline earth metal salts of lower carboxylic acids, alkali metal bicarbonates and alkaline earth metal bicarbonates, alkali metal (di) phosphorus The desired product (I) is preferably reacted directly in the presence of a base selected from the group consisting of oxyhydrogen salts and alkaline earth metal (di) hydrogen phosphate salts and bases having a pKa value of 4 to 9. It was found to give in yield.

In the following description, the term "C _1-6 alkyl" refers to all straight-chain and branched-chain primary, secondary and tertiary alkyl radicals having up to 6 carbon atoms. It should be understood as meaning those having atoms. Correspondingly, “C _1-6 alkoxy” and “(C _1-6 alkoxy) -carbonyl” mean ether and ester functional groups composed of C _1-6 alkyl and oxygen, or oxygen and carbonyl. Similarly, “(C _1-6 alkoxy) -C _1-6 alkyl” is the same as
_It should be understood that it refers to an alkoxyalkyl group formed by replacing a hydrogen atom of a _1-6 alkyl with a C _1-6 alkoxy, ie, for example, methoxymethyl or ethoxymethyl.

In the following, "aryl" is to be understood as meaning, in particular, mono- or polycyclic systems, for example phenyl, naphthyl, biphenylyl or anthranyl. These may be one or more of the same or different substituents, for example a lower alkyl group such as methyl, a halogenated alkyl group such as trifluoromethyl, a lower alkoxy group such as methoxy, or methylthio or ethane. It is to be understood that lower alkylthio (alkanesulfanyl) or alkanesulfonyl groups such as sulfonyl are meant. The term "substituted phenyl" is to be understood as meaning, in particular, groups such as fluorophenyl, methoxyphenyl, toluyl or trifluoromethylphenyl. The substituent is
It is preferable to be placed at the para position. In correspondence with the "arylalkyl" means a lower alkyl group and a country C _1-6 alkyl group, the hydrogen atom, a group formed by replacing one aryl group as defined above Then it should be understood.

The 2,3-dichloropyridine (II) used as the starting material is a known compound or could be prepared in a manner analogous to the method for preparing known compounds. (Eg, LA Paquette, En
cyclopedia ofReagents for
Organic Synthesis, John Wiley & S
ons, New York, 1995 and CH-A664754) 2,3-Dichloro-5- (methoxymethyl) pyridine is novel and forms part of the subject of the present invention.

Preferably, according to the novel process, methyl or ethyl esters (R = Me, Et) are prepared using methanol or ethanol as alcohol (III).

Similarly, the positions 4 and 6 of the pyridine ring are not substituted (R ¹ = R ³ = H) pyridine-2,3-
The production of carboxylic esters is preferred.

Particularly preferred is pyridine-2,3
-In the carboxylic acid ester (I), 5 of the pyridine ring
In which the position (R ² ) is hydrogen, a (C _1-4 alkoxy) -carbonyl group or a (C _1-4 alkoxy) -methyl group.

The catalytically active palladium-diphosphine complex is preferably palladium in the form of finely divided elements (eg palladium on activated carbon, Pd
(II) a salt (eg chloride or acetate) or a suitable P
The d (II) complex (eg, dichlorobis (triphenylphosphine) palladium (II)) is reacted with diphosphine to form it in situ. Particularly preferred are palladium (II) acetate and dichlorobis (triphenylphosphine) palladium (I
Combination with I). In each case, palladium is 0.02 to 5 mol% based on the halogen compound (II).
Pd (II), or 0.5-5 mol% Pd (O) (P
It is preferred to use an amount of (as d / C). Diphosphine is preferably used in an excess amount (based on Pd), and is suitably used in an amount of 0.2 to 10 mol% based on the halogen compound (II).

The alcohol (III) can simultaneously serve as a solvent. If necessary, additional solvents may be used. Possible additional solvents include both relatively non-polar solvents such as toluene or xylene, or polar solvents such as acetonitrile, tetrahydrofuran or N, N-dimethylacetamide.

The base used is preferably an alkali metal acetate. Particularly preferred are sodium and potassium acetate.

[0024] The reaction temperature is preferably 80 to 250 ° C.

The pressure of carbon monoxide is preferably 1 to 50
Pressure.

The reaction time is determined by various factors, especially the reactivity of the compound used and the concentration ratio, and is typically several hours. Excessively long reaction times will cause secondary reactions since the two chlorine atoms of dichloropyridine (II) are subsequently replaced. Therefore, it is advantageous to monitor the progress of the reaction by an appropriate analytical method (for example, GC), and to terminate the reaction when the concentration of the product is maximized.

[0027]

The following example illustrates how the method of the present invention is practiced.

Example 1 Diethylpyridine-2,3-dicarboxylate (I, R = Et, R ¹ = R ² = R ³ = H) 1.52 g (10 mmol) of 2 was added to a metal autoclave. , 3-Dichloropyridine (Fulka), 166mg
(0.3 mmol) of 1,1′-bis (diphenylphosphino) ferrocene, 22.4 mg (0.1 mmol) of palladium (II) acetate, 1.72 g (21 mmol) of sodium acetate and 25 ml of ethanol were introduced. . After the autoclave was repeatedly flushed with carbon monoxide, the carbon monoxide pressure was increased to 15 atmospheres and the reaction mixture was heated to 135 ° C. and reacted for 2.5 hours. The reaction mixture is concentrated under vacuum and the residue is taken up in hexane / ethyl acetate (3: 1)
Was chromatographed on silica gel 60 using.

Yield: 0.945 g (85%) of a colorless oil ¹ H NMR (CDCl ₃ ) δ = 8.75 (d, 1H); 8.19 (d, 1H); 7.47 (dd, 1H). 4.48 (q, 2H); 4.39 (q, 2H); 1.44 (t, 3H); 1.39 (t, 3H). MS (m / z): 223 (M ^<+> ); 179; 150; 122; 107;

Example 2 Trimethylpyridine-2,3,5-tricarboxylate (I, R = Me, R ¹ = R ³ = H, R ² = COOMe) In the same manner as in Example 1, 2 0.06 g (10 mmol) of methyl-5,6-dichloronicotinate (II, R ¹ = R ³ =
H, R ² = COOMe), 128 mg (0.3 mmol) of 1,
4-bis (diphenylphosphino) butane, 14.0
mg (20 μmol) of dichlorobis (triphenylphosphine) palladium (II) and 2.46 mg (30 mmol) of sodium acetate in 25 ml of methanol
At 55 ° C. (bath temperature) and carbon monoxide pressure 15 atm,
The reaction was performed for 6 hours. GC analysis of the reaction mixture showed 100% conversion and 77% yield.

_3. Yield of isolated product: 800 mg (50%) of a yellow oil ¹ H NMR (CDCl ₃ ) δ = 9.31 (s, 1H); 8.78 (s, 1H); 01 (s, 3H); 4.00 (s, 3H); 3.97 (s, 3H). MS (m / z): 253 (M ^<+> ); 223; 222; 195; 194; 165; Example 3 2,3-Dichloro-5- (methoxymethyl) pyridine (II, R ¹ ＲR ³ ＨH, R ² ＣＨCH ₂ OMe) 4.11 g (20.9 mmol) of 2 in an argon atmosphere , 3
-Dichloro-5- (chloromethyl) pyridine (2,3-
Prepared from dichloro-5- (hydroxymethyl) pyridine by reaction with thionyl chloride)
To a solution in ml of methanol, 4.14 g (23 mmol) of sodium methylate (30% solution in methanol) were added dropwise at room temperature over 5 minutes. The reaction mixture was heated to 60 C for 3 hours. After the reaction had ended, the solvent was distilled off, the residue was mixed with 100 ml of water and extracted with dichloromethane (3 × 75 ml). The organic phase was dried over magnesium sulfate and brought to a boil.

Yield: 4.06 g (90.4%) of a yellow oil, 90.8% pure (GC). To analyze the product, use hexane / ethyl acetate (3: 1) on silica gel. Chromatographed.

¹ H NMR (CDCl ₃ ) δ = 8.25 (s, 1H); 7.78 (s, 1H); 4.46 (s, 2H); 3.43 (s, 3H). MS (m / z): 192 (M ^<+> ); 176; 161; 148; 124;

Example 4 Dimethyl-5- (methoxymethyl) pyridine-2,3-
Dicarboxylate (I, R = Me, R 1 = R 3 = H, R 2 = CH 2 OMe) in a manner similar to Example 1, 1.92 g of (10 mmol) 2,3-dichloro-5- ( Methoxymethyl) pyridine (prepared according to Example 3), 166 mg (0.3 mmol)
1,1-bis (diphenylphosphino) ferrocene,
14 mg (20 μmol) of dichlorobis (triphenylphosphine) palladium (II) and 2.46 g (30 mmol)
Of sodium acetate in 25 ml of methanol
The reaction was carried out at 160 ° C. (bath temperature) at a carbon monoxide pressure of 15 atm for 24 hours. GC analysis of the reaction mixture
The conversion was 100% and the yield was 83%.

Yield of isolated product: 500 mg (41%) of a yellow oil, 97% pure (GC) ¹ H NMR (CDCl ₃ ) δ = 8.70 (s, 1H); 8.15 (s, 1H) 4.57 (s, 2H); 4.00 (s, 3H); 3.92 (s, 3H); 3.43 (s, 3H). MS (m / z): 239 (M ^<+> ); 209; 181; 151;

Example 5 Dimethyl-5- (methoxymethyl) pyridine-2,3-
Dicarboxylate (I, R = Me, R 1 = R 3 = H, R 2 = CH 2 OMe) The reaction temperature was increased to 180 ° C. (bath temperature), except that a shortened reaction time of 4 hours, Example The same procedure as described in 3 was repeated. As a result of GC analysis of the reaction mixture, the conversion was 100% and the yield was 79%.

Yield of isolated product: 750 mg (58%) of a yellow oil, purity (GC) 92.4%.

Example 6 Dimethyl-5- (methoxymethyl) pyridine-2,3-
Dicarboxylate (I, R = Me, R ¹ = R ³ = H, R ² = CH ₂ OMe) 4.4 mg (20 μmol) of palladium acetate (II) in place of dichlorobis (triphenylphosphine) palladium (II) ) Was repeated, except that ()) was used. Reaction temperature is 160-170 ° C
(Bath temperature) and the reaction time was 5 hours. As a result of GC analysis of the reaction mixture, the conversion was 100% and the yield was 90%.

Yield of isolated product: 740 mg (61%)
Yellow oil, purity (GC) 100%.

Example 7 Dimethyl-5- (methoxymethyl) pyridine-2,3-
Dicarboxylate (I, R = Me, R ¹ = R ³ = H, R ² = CH ₂ OMe) The procedure of Example 6 was repeated except that 2.94 g (30 mmol) of potassium acetate was used instead of sodium acetate. The same procedure was repeated as described. The reaction temperature was 170 ° C. (bath temperature), and the reaction time was 3 hours. G of reaction mixture
As a result of C analysis, the conversion was 100% and the yield was 90%.

Example 8 Diethyl-5- (methoxymethyl) pyridine-2,3-
Dicarboxylate (I, R = Et, R ¹ = R ³ = H, R ² = CH ₂ OMe) In the same manner as in Example 3, 1.92 g (10 mmol) of 2,3-dichloro-5- ( Methoxymethyl) pyridine,
166 mg (0.3 mmol) of 1,1′-bis (diphenylphosphino) ferrocene, 14.0 mg (20 μmol) of dichlorobis (triphenylphosphine) palladium (II) and 2.46 g (30 mmol) of sodium acetate The reaction was carried out in 175 ° C. (bath temperature) at a carbon monoxide pressure of 15 atm for 4 hours in 25 ml of ethanol. GC analysis of the reaction mixture showed 100% conversion,
The yield was 79%.

Yield of isolated product: 920 mg (67%) of a yellow oil, purity (GC) 98.1% ¹ H NMR (CDCl ₃ ) δ = 8.70 (s, 1H); 8.15 ( 4.55 (s, 2H); 4.46 (q, 2H); 4.40 (q, 2H); 3.44 (s, 3H); 1.42 (t, 3H); 1.38 (t, 3H). MS (m / z): 267 (M ^<+> ); 236; 223; 194; 151; 123.

Example 9 Diethyl-5- (methoxymethyl) pyridine-2,3-
Dicarboxylate (I, R = Et, R ¹ = R ³ = H, R ² = CH ₂ OMe) 4.4 mg (20 μmol) of palladium acetate (II) in place of dichlorobis (triphenylphosphine) palladium (II) ) And the amount of sodium acetate was 1.72 g (21
The same procedure as described in Example 8 was repeated, except that the amount was reduced to (mmol). The reaction temperature was 155 ° C. (internal temperature), and the reaction time was 2 hours. G of reaction mixture
As a result of C analysis, the conversion was 100% and the yield was 88%.

Yield of isolated product: 950 mg (67%)
Yellow oil, purity (GC) 94%.

Example 10 Diethyl-5- (methoxymethyl) pyridine-2,3-
Dicarboxylate (I, R = Et, R ¹ = R ³ = H, R ² = CH ₂ OMe) Example 9 was repeated except that the reaction temperature was 145 ° C. (internal temperature) and the reaction time was 5 hours. The same procedure was repeated as described. As a result of GC analysis of the reaction mixture, the conversion rate was 1
The yield was 95%.

Yield of isolated product: 1100 mg (78.7
%) Yellow oil, purity (GC) 95.6%.

Example 11 Diethyl-5- (methoxymethyl) pyridine-2,3-
Dicarboxylate (I, R = Et, R ¹ = R ³ = H, R ² = CH ₂ OMe) Same as the method described in Example 9 except that 11 mg (50 μmol) of palladium (II) acetate was used. The operation was repeated. As a result of GC analysis of the reaction mixture, the conversion was 100%,
The yield was 98%.

Yield of isolated product: 1260 mg (90%)
Yellow oil, purity (GC) 95.4%.

 ──────────────────────────────────────────────────の Continued on the front page (72) Inventor Jean-Paul Rodui Switzerland Canton Valis CH-3979 Gourne Lois (no address)

Claims (7)

[Claims] 1. A compound of the general formula Wherein, R is C _1-6 alkyl, C _3-6 cycloalkyl, aryl or arylalkyl, to no R ¹ R
³ independently of one another are hydrogen, C _1-6 alkyl, fluorinated C _1-6 alkyl, C _1-6 alkoxy, (C _1-6 alkoxy) -C _1-6 alkyl or (C _1- alkyl ₆ alkoxy)-
Carbonyl. And a method for producing a pyridine-2,3-carboxylic acid ester of the general formula: [Wherein, R ¹ to R ³ have the meanings described above. 2
The halopyrimidine is converted to carbon monoxide and a compound of the general formula [Wherein, R has the meaning described above. ], Palladium and a general formula Wherein R ⁴ to R ⁷ are each independently phenyl, substituted phenyl, C _1-6 alkyl or C _3-6 cycloalkyl, and Q is a 1,1′-ferrocenediyl group or a formula-[ CH ₂ ] _n- (where n is 3 or 4)
It is a group of. Catalytically active complex with diphosphine, and alkali metal and alkaline earth metal salts of lower carboxylic acids, alkali metal hydrogencarbonates and alkaline earth metal hydrogencarbonates, alkali metal (di) hydrogenphosphate And a base selected from the group consisting of alkaline earth metal (di) hydrogen phosphate and a base having a pKa value of 4 to 9. 2. The method according to claim 1, wherein R is methyl or ethyl. 3. The method according to claim 1, wherein R ¹ and R ³ are hydrogen. 4. The method according to claim 1, wherein R ² is hydrogen, (C _1-4 alkoxy) -carbonyl or (C _1-4 alkoxy) -methyl. 5. The catalytically active palladium complex comprises diphosphine (IV) and palladium (II) acetate or dichloro-bis (triphenylphosphine) palladium (I).
The method according to any of claims 1 to 4, characterized in that it is produced in situ from (I). 6. The process according to claim 1, wherein the base used is an alkali metal acetate, preferably sodium acetate or potassium acetate. 7. A 2,3-dichloro-5- (methoxymethyl) pyridine.